1. Field of the Invention
The present invention relates to fluorochemical blood substitutes used for preserving mammalian tissue having lysophosphatidyl compounds in non-toxic concentrations. More specifically, the invention relates to aqueous fluorochemical emulsions of a fluorochemical and an emulsifier useful as oxygen delivery agents and methods of preserving cardiac tissue in investigational and clinical settings, particularly those settings involving in vivo transfusion, cardiac and other organ preservation, and in vitro organ perfusion.
The need for clinically safe and effective oxygen-carrying media for use as red cell substitutes ("blood substitutes" or "artificial blood") is undisputed. Some of the potential uses for such media include (a) support of organs in vitro prior to transplantation or in vivo during surgery, (b) support of organs or whole animals during experimental investigations, (c) enhancing oxygen delivery to ischemic organs in vivo, (d) enhancing oxygen delivery in poorly vascularized tumors to increase the efficacy of radiation therapy, (e) general transfusion uses, during both routine and emergency situations, (f) diagnostic imaging, and (g) culturing cells.
Blood substitute research is currently focused on hemoglobin-based preparations and fluorochemical emulsions. Fluorochemical emulsions are believed to have major advantages over hemoglobin-based red cell substitutes. Problems associated with hemoglobin preparations include a limited supply of starting material, lack of biological purity, limited ability to deliver oxygen in the presence of erythrocytes, nephrotoxicity, short biological retention times, uncertainty regarding the presence of infectious agents, the large amount of potentially free iron that could propagate oxygen free radical reactions, the presence of unidentified vasoconstrictor contaminants, and hemoglobin inhibition of endothelial derived relaxing factor (EDRF)--mediated vasodilation.
In comparison, fluorochemical emulsions are chemically synthesized, can be made biocompatible, and are free of infectious agents. They dissolve oxygen in direct proportion to inspired oxygen fraction (FiO.sub.2) thereby increasing plasma oxygen capacity. Fluorochemical emulsions of several compositions have been shown to deliver oxygen effectively in a variety of settings. A common emulsifying agent is phospholipid from natural sources such as egg yolk. It has been determined that the phospholipids of the prior art fluorochemical emulsions contain lysophosphatidyl compounds in toxic concentrations. The removal of these compounds greatly enhances the preservation ability of the emulsions.
2. Information Disclosure
Schweighardt, U.S. Pat. Nos. 4,895,876 and 4,866,096, describe stable aqueous emulsions of a perfluorochemical, a phospholipid, and a triglyceride of fatty acids which has enhanced stability, diminished particle size and heightened tolerance by biological systems. The patent claims to provide an advance over prior art artificial blood media to provide decreased particle size, increased stability and longer shelf life for an oxygen transport media useful in mammals.
The physiological impact of lysophospholipids has been studied. Fink K. L., and Gross, R. W., 1984, Modulation of canine myocardial sarcolemmal membrane fluidity by amphiphilic compounds, Circulation Research 55:585-594, 1984; Corr, P. B. et al., 1984, Amphipathic metabolites and membrane dysfunction in ischemic myocardium, Circulation Research, 55:135-154 and Han, X. and Gross, R. W., 1991, Modulation of cardiac membrane fluidity by amphiphilic compounds and their role in the pathophysiology of myocardial infarction, Drug and Anesthetic Effects on Membrane Structure and Function, Aloia, Curtain and Gordon (Eds) New York Wiley-Liss, at pages 225-243.
The only fluorochemical emulsion acceptable for clinical use at this time is Fluosol-DA which is described in Blood Substitutes and Plasma Expanders, Eds. Jamieson and Greenwalt, A. R. Liss Co., 1978, pages 1-26 (see page 13, Table VI) and in Cleman, M. et al. Prevention of ischemia during percutaneous transluminal coronary angioplasty by transcatheter infusion of oxygenated Fluosol DA 20%, Circulation, 74(3): 555-562, 1986.